Drug abuse is very costly in terms of human misery, economic loss, crime and death. Current attempts to alleviate these problems have been hampered by a lack of understanding about the neurochemical and neuroanatomical substrates of drug abuse behavior. The existing literature suggests that animal self-administration of d-amphetamnine (d-A) may be mediated by the putative neurotransmitters dopamine (DA), norepinephrine (NE), and 5-hydroxytryptamine (5HT) in the nucleus accumbens septi (NAS) and striatum (ST). However, the evidence has been indirect, often contradictory and, in some cases, very sparse. One of the major problems in determining the effects of drug self-injection on brain chemistry is that, due to the difficulty and time-consuming nature of obtaining animals with stable self-injection behavior, it is impractical to sacrifice the subjects in order to measure some index of neurochemistry. The research described herein is designated to circumvent this problem by testing the feasibility of perfusing the NAS or ST of rats who are simulatenously self-injecting d-A. Rats will be implanted with a silastic catheter in the jugular vein and with a cannula base with the tip of the needle tubing placed in the NAS or ST. After they recover from surgery, the rats will be perfused with an artificial cerebrospinal fluid while they are allowed to self-inject d-A. Sequential 10 min samples of perfusate will be collected and assayed for DA, NE, 5HT and their metabolites by high performance liquid chromatography with electrochemical detection. Changes in the perfusate content of these compounds will be correlated with drug self-administration. In this way, we will be able to determine if: 1) the NAS or ST can be perfused while an animal self-injects d-A; and 2) the efflux of DA, NE, 5HT or their metabolites from the NAS or ST is altered by d-A self-administration. The long-term objectives of this research include: 1) obtaining data relevant to current controversies in this field; 2) determining the effects of other drugs of abuse (e.g., nicotine, morphine) on the efflux of DA, NE, 5HT and their metabolites from brain; 3) investigating the importance of other neurotransmitters or neuromodulators (e.g., endorphins, trace amines) in self-administration behavior; 4) testing other neuroanatomical sites which might play a role in drug self-injection; and 5) ultimately discovering what neurochemical constituents and neuroanatomical sites are important to drug self-injection in animals may lead to better prevention and treatment of drug abuse as well as better prediction of future abused drugs.